Revista de diagnóstico y biomarcadores moleculares

Selection of Sensitive Methylation Markers for the Detection of Non-small Cell Lung Cancer

Abstract

Xia Zhao, Jin Jen, Tobias Peikert, Eric Edell, Shulan Tian, Ping Yang, Yajue Huang and Hongzhi Zou

Introduction: While early-stage lung cancer is curable by surgical resection, most patients are diagnosed with advanced- stage disease. Annual low-dose computed tomography screening decreases lung cancer mortality, however effective biomarkers to address the high false positive rate and to better define high risk individuals are lacking. This study was designed to identify potential DNA methylation markers for the detection of non-small cell lung cancer, the most common type of lung cancer.

Methods: 152 candidate methylation genes were first investigated in lung cancer cell lines and a pilot set of lung tissues. Five promising methylated genes, DMRTA, HOXA9, ZIC4, HOXA7, and SIX3, were selected and further validated in 150 non-small cell lung cancers and 142 tumor-free surrounding lung tissues using the quantitative methylation-specific PCR.

Results: Methylation levels of DMRTA2, HOXA9, ZIC4, HOXA7, and SIX3 were significantly higher in tumors compared to tumor-free surrounding lung tissues (P<2.2e-16 for all). Receiver operation curve analysis showed that methylation of DMRTA2, HOXA9, ZIC4, HOXA7, and SIX3 identified 93%, 91%, 89%, 81%, and 59% of non-small cell lung cancers (n=150) with a specificity of 95%. Comparing tumors to tumor-free surrounding lung tissues, area under the curve values were 0.967, 0.955, 0.950, 0.904, and 0.819, respectively. The predicted area under the curve value after combining DMRTA2 and HOXA9 was 0.971. Methylation levels of these genes were not correlated to cancer stages (P>0.05).

Conclusion: We identified a group of highly sensitive and specific methylation markers in non-small cell lung cancer. These markers are potential valuable candidates to improve the performance of lung cancer screening.